Conjugation of drugs to antibodies, either directly or via linkers, involves a consideration of a variety of factors, including the identity and location of the chemical group for conjugation of the drug, the mechanism of drug release, the structural elements providing drug release, and the structural modification to the released free drug. In addition, if the drug is to be released after antibody internalization, the mechanism of drug release must be consonant with the intracellular trafficking of the conjugate.
While a number of different drug classes have been tried for delivery via antibodies, only a few drug classes have proved efficacious as antibody drug conjugates, while having a suitable toxicity profile.
Natural products FR901463, FR901464, and FR901465 were reported to have potent inhibitory activities against human cancer cell lines and efficacies in several xenograft tumor models. (Journal of Antibiotics (1996), 49(12), 1204-1211.) The natural product FR901464 and its methyl ketal, designated spliceostatin A, were recently reported to inhibit the spliceosome by interaction with SF3b, which is a component of the essential subcomplex, U2 snRNA. (Nature Chemical Biology (2007), 3(9), 576-583; Nature (London, United Kingdom) (2010), 468(7324), 664-668.)